Action of the Oxedrine and Tolazoline in Alpha-Adrenergic Receptor At

Home , Hexoprenaline

Islami et al., 1:4 http://dx.doi.org/10.4172/scientificreports.235 Open Access Open Access Scientific Reports Scientific Reports Research Article OpenOpen Access Access Action of the Oxedrine and Tolazoline in Alpha-Adrenergic Receptor at Patients with Increased Bronchial Reactibility Hilmi Islami1*, Mehmedali Azemi2, Emir Behluli3, Feim Haliti4, Arta Dauti4, Shpend Dragusha4 and Bedri Abdullahu4 1Department of Pharmacology, Faculty of Medicine, University of Prishtina, Clinical Centre, Prishtina, Kosova 2Department of Pediatric, Faculty of Medicine, University of Prishtina, Clinical Centre, Prishtina, Kosova 3Department of Pediatric, Faculty of Medicine, University of Prishtina, Clinical Centre, Prishtina, Kosova 4Department of Pharmacy, Faculty of Medicine, University of Prishtina, Clinical Centre, Prishtina, Kosova

Abstract

Objective: In this work, effect of Oxedrine stimulation in alpha1 adrenergic receptor and the effect of Tolazoline

as a blocker of alpha2 adrenergic receptor in patients with increased bronchial reactibility of respiratory ways were studied. Methods: Parameters of the lung function were determined by Body plethysmography. Raw and ITGV were registered and SRaw was calculated as well. Aerosolization is done with standard aerosolizing machine - Asema. Patients, in order to make a detailed study, were divided in two groups: middle reactor and severe reactor.

Results: Results obtained from this research, show that stimulation of alpha1 adrenergic receptor with Oxedrine tartrate (120 mg-aerosol) caused an increase of the airways specific resistance after 60 minutes, but it has not undergone a significant change (p > 0.1) in comparison to the inhalation of hexoprenaline (and Ipratropium bromide

(2 inh x 0.25 mg) (p < 0.01). Blockage of the alpha2-adrenergic receptor with Tolazoline hydrochloride (20 mg - aerosol) as well has not changed the airways permeability in a significant manner (p > 0.1)

Conclusion: This suggests that the activity of alpha1 and alpha2 adrenergic receptors in the smooth musculature

are not a primary mechanism that cause bronchial reaction, in comparison to agonists of beta2 adrenergic receptor and cholinergic antagonists which emphasize their significant action in the reduction of specific resistance of airways.

Keywords: Oxedrine; Tolazoline; Hexoprenaline; Ipratropium inhaled phenylephrine, as an agonist of alpha-adrenergic receptor, does not cause a significant effect in the airways resistance. Despite this Introduction response, this suggests an even more detailed study of this receptor in Airways smooth musculature tonus is under the influence of adjusting of the bronchomotor tonus [9]. different neurotransmitters, hormones, drugs, and mediators which Activation of action of some of the above mentioned factors can manifest their action by connecting to the surface of a specific receptor be initiated also by the outside environment factors such are physical in airways smooth musculature cells. All these factors, related to the activity or exposure to the cold air. Actually, it is supposed that during tonus of airways musculature, manifest their action by an excitatory the exposure to the cold air, bronchoconstriction can be initiated effect (agonist) and inhibitory effect (antagonist) during binding to the respective receptor localized in airways musculature cells [1].In the through the increase of the alpha adrenergic receptors’ activity. mechanism of bronchial hyper-reactibility, important role has also the Therefore, this fact has enhanced the role of alpha adrenergic receptors modulator substances released following the inflammatory processes in the mechanism of asthma. and other substances following the degranulation process of mastocyte Researches in experimental animals and in isolated segments [2]. of human bronchi have proved the presence of a small number of In adjusting of the airways caliber, cholinergic nerve system alpha-adrenergic receptors. These researches have also proved that plays the predominant role. Supposedly, in asthmatic patients it is the presence of this receptor in pulmonary diseases is increased by manifested with a hyperactivity of the cholinergic system due to the suggesting the role of this receptor in the patho-physiologic mechanism fact that anticholinergic drugs may cause severe bronchodilator effect of bronchial asthma [10]. Up to date, some aspects of patho-physiology, in these patients whilst this effect does not manifest in healthy persons. diagnoses, treatment, and prophylaxis in asthma have remained yet Although, mechanism of this hyperactivity of this system is not yet unexplained [11]. entirely known [3,4]. In patients with increased bronchial reactibility, the importance of alpha-adrenergic system is not fully clarified [5]. Many researchers *Corresponding author: Hilmi Islami, MD PhD, Institute of Clinical Pharmacology accentuate that in the group of selected asthmatic patient, without and Toxicology, Faculty of Medicine, Prishtina University, Clinical Centre, Mother Theresa Str., 10000, Prishtina, Kosova; E-mail address: [email protected] effects of other medicaments, administration of alpha-adrenergic antagonist leads towards the improvement of airways function [6]. Received March 12, 2012; Published August 16, 2012 Alpha-adrenergic antagonist (e.g. indoramin) causes bronchodilation, Citation: Islami H, Azemi M, Behluli E, Haliti F, Dauti A, et al. (2012) Action of the due to the blocking of alpha-adrenergic receptors, and can be useful Oxedrine and Tolazoline in Alpha-Adrenergic Receptor at Patients with Increased therapeutics for a certain asthmatic population [7]. It remains unclear Bronchial Reactibility. 1: 235. doi:10.4172/scientificreports.235 whether these results are caused by the blockage of stimulation of Copyright: © 2012 Islami H, et al. This is an open-access article distributed under alpha-adrenergic receptors of mastocytes or airways smooth muscles the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and [8]. Some researchers have verified that in the group of asthmatics source are credited.

Volume 1 • Issue 4 • 2012 Citation: Islami H, Azemi M, Behluli E, Haliti F, Dauti A, et al. (2012) Action of the Oxedrine and Tolazoline in Alpha-Adrenergic Receptor at Patients with Increased Bronchial Reactibility. 1: 235. doi:10.4172/scientificreports.235

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In order to evaluate the importance of the alpha-adrenergic system in the cabin. In the end of the rest expirium, when there is no flow, in the regulation of the bronchomotor tonus in patients with middle equation of pressure in alveoli and bronchi with pressure in the mouth and severe bronchial reactibility, effects of the Oxedrine (stimulator happens very fast. Due to this, measurement of the pressure in the of alpha1-adrenergic receptor) and Tolazoline (blocker of alpha2- mouth provides accurate information for the alveolar pressure. The adrenergic receptor) in this adjustment were researched, in comparison difference of the pressure in the mouth and at the cabin is checked by to the effects of the beta2-adrenergic receptor (Hexoprenaline) and two sensitive manometers. anticholinergic substances (Ipratropium bromide). Overall quantity of the volume of the intrathoracic gas (ITGV) Material and Methods was measured with the plethysmography method, including closed gas that do not ventilate. If the residual functional capacity is taken This study project was approved by the Ethic Committee of from the ITGV, obtained by the plethysmography method, we will the Medical Faculty in Prishtina. Selection of patients for this study gain information regarding quantity of closed gas due to a severe was done based on the data from anamnesis, clinical-laboratory obstruction, cystic lungs or pneumothorax. In healthy persons with a ascertainments, and functional pulmonary examinations. Study normal pulmonary function, volume of the intrathoracic gas is equal involved overall 21 patients. At least 48 hours prior research of with the residual functional capacity. From the beta and alpha angles, bronchial reactibility response, patients has not administered any of with the help of tables, values of the airways resistance and volume the bronchodilatory substances. Examined were informed regarding of the intrathoracic gas are calculated. From gained values, specific manner of the functional pulmonary examinations. Patients were rezistance was calculated (SRaw = Raw × ITGV). Raw and the SRaw suffering from asthma, with or without being followed by bronchitis. were taken for analyses. Research of the bronchial response to different Average of the disease lasting was 11 ± 6 years (from 4-20 years). substances was done with the measurement of Raw and the SRaw as Average of their age was 44 ± 7 years (from 29 - 45 years), whereas very sensitive indicators, compared to the parameters calculated from average of relative weight was 70 ± 7% (from 65 - 72%). The aim of the MEF curve, and therefore they are very important in the research the examination was explained to each of the patients in advance. of the bronchoconstriction and bronchodilation. Realized values Pulmonary function was defined at the rest, which was composed of of MEF25, MEF50, show that calculated parameters from the curve measurement of vital capacity (VC), forced expiratory volume (FEV1), flow-volume during the volumes in small parts of the lung are more resistance in the airways (Raw) and intrathoracic gas volume (ITGV). sensitive than classic indicators of the measured obstruction with the

In addition to the measurement of these parameters of the spirometric examinations (FEV1, 100 x FEV1/FVK). Comparison of pulmonary ventilator function, Maximum Expiratory Flow-Volume direct variables obtained from Raw, and SRaw and indirect indicators Curve (MEF) was also defined. Curve (MEF) was registered ina of the airways obstruction (FEV1, 100 x FEV1/FVK, RME25, and seating position with same breathing action as the forced vital capacity. RME50) is very important in patients with bronchial asthma and Person breathed with mouth (closed nose), through a muzzle of the lung obstructive diseases. Basic features and those of the pulmonary pneumotachograph. function of researched are provided in Table 1. Airflow was measured with the help of the pneumotachograph, First group of patients, in order to make a detailed study, whereas the volume through a volume-integrator. MEF curve was was divided in: middle reactor and severe reactor. Following the registered in the X-Y writer (Hewlett-Packard). measurement of respective parameters of lung function, patients were administered Oxedrine tartrate as aerosol (120 mg/3 ml/5 min) Flow was registered in the ordinate, and the volume in abscissa. through inhalator Asema with a possibility of aerosolization of 0.5 ml Several parameters were calculated, whereas Maximum Expiratory per minute. Immediately after the inhalation, Raw and ITGV, arterial Flow was taken for analyses after it has expirated 25, 50 and 75% of VC pressure, and pulse were measured and measurements were repeated 75 (MEF25, MEF50, and MEF - l/s.). after 15, 30 and 60 minutes following the inhalation. These parameters were analyzed since they are situated in the part Same patients, after defining of the lung function parameters, of the curve which primarily depends on mechanic features of the administered Hexoprenaline (2 inh. x 0.2 mg), or Ipratropium bromide lungs and not from the expiratory force and also because of being more (2 inh. x 0.25 mg), and afterwards Raw and ITGV, arterial pressure, and sensitive than FEV1 in measurement of bronchial reactibility. Prior to pulse were measured and repeated after 15, 30 dhe 60 min. the provoking of bronchoconstriction, at least two reproducible MEF curves, blood pressure, and pulse were measured as well. Second group of patients, in order to make a detailed study, was also divided in: middle reactor and severe reactor. Following the General resistance of the airflow in the airways (Raw) and the defining of respective parameters of lung function, patients were volume of the intrathoracic gas (ITGV) were researched in patients. The administered Tolazoline hydrochloride as aerosol (20 mg/3 ml/5 min) patient was placed in the cabin of the plethysmograph that was closed through inhalator Asema with a possibility of aerosolization of 0.5 ml in a hermetic manner, and was connected to the pneumotachograph per minute. Immediately after the inhalation, Raw and ITGV, arterial through an oral mask in order to breathe the air. During the inspirium, pressure, and pulse were measured and measurements were repeated with an expansion of the sternum, air in the cabin compresses; whereas, after 15, 30 and 60 minutes. it decompresses in the lung, namely it comes to the decrease of the intrathoracic pressure with the proportional increase of the pressure Afterwards, following the measurement of lung function in the cabin. During the expirium, the opposite situation appears: parameters, patients were administered Hexoprenaline (2 inh. x 0.2 increase of intraalveolar pressure and proper decrease of the pressure mg), or Ipratropium (2 inh. x 0.25 mg), then Raw and ITGV, arterial

n Age(v) Height (cm) Mass (kg) VC (%) FEV1 (%) Raw (kPa L/s) ITGV (L) 21 44.12 ± 1.30 179.19 ± 1.17 70.81 ± 0.78 101.21 ± 3.2 106.35 ± 3.46 0.11 ± 0.01 4.08 ± 0.14 Table 1: Basic characteristics and pulmonary function in examined.

Page 3 of 8 pressure, and pulse were measured and similarly were repeated after in arterial pressure and pulse are not significant. 15, 30 and 60 minutes. Discussion In order to observe changes in the airways permeability after inhaling of aerosol of Oxedrine, Tolazoline, and Hexoprenaline or Importance of adrenergic action in the regulation of bronchomotor Ipratropium, index of changes in percentage was calculated, namely tonus is not quiet known. They can act through beta or alpha - Raw, ITGV and SRaw (%P) values were calculated as follows: adrenergic receptor in the smooth musculature of airways and modify their permeability [12]. Initial values - minimal value after the inhaling of certain substance Results of this research, in patients with bronchial reactibility Ind. of decrease = ------× 100 (middle and severe reactor), shows that stimulation of alpha1 - Initial values adrenergic receptor with Oxedrine tartrate (120 mg-aerosol) and their blockage with Tolazoline hydrochloride (20 mg-aerosol) does Hypothesis that changes in the adrenergic system is not important not change significantly (p > 0.1) the bronchomotor tonus of the and not related to the development of bronchial asthma or other tracheobronchial system, in comparison to Hexoprenaline (beta2- obstructive diseases which are not related to the allergic manifestation adrenergic agonist) and Ipratropium bromide (anticholinergic), which were utilized. are very effective in removal of increased bronchomotor tonus, by causing significant decrease of the resistance (Raw), respectively of Obtained results were grouped and analyzed. Statistic processing of specific resistance (SRaw) (p < 0.01). This research was done also to data included the defining of the average values (X), standard deviation examine whether the constriction of smooth respiratory musculature (SD), standard mistake (SEM), and testing of the significance of changes is caused by two sub-types of alpha adrenergic receptors (alpha and in between groups of Patients treated with Propranolol, Tolazoline and 1 alpha adrenergic). Regarding this, there are neither earlier reports control with Hexoprenaline. 2 by which to prove two sub-types of alpha adrenergic receptors in Obtained results were tested by a test (t-test) in order to ascertain the airways musculature nor reports over effects of clonidine in the significant changes in between examined groups. Data were processed receptors of smooth musculature [13]. Earlier researches have not with a computer statistic sofware Instat-3 and Statistica for Windows. demonstrated any of the alpha2 adrenergic receptor in the respiratory epithelial surface. Lately, experiments in vivo show that clonidine Results intermediates an inhibitor control over the vagal excitation activity Results of this research, in patients with bronchial reactibility [14,15]. Inhibitory effect of the clonidine in bronchoconstriction might be induced with straight bronchodilation, or through inhibition of the (middle reactor and severe reactor), show that stimulation of alpha1 - adrenergic receptor with Oxedrine tartrate (120 mg-aerosol) vagal reflex, or with the inhibition of the release of histamine asan causes an increase of airways specific resistance after 60 minutes and inhibition caused by an antigen [16]. In the group of the researched their blockage with Tolazoline hydrochloride (20 mg-aerosol) does patients with middle and severe bronchial reactibility, we couldn’t not change significantly (p > 0.1) the bronchomotor tonus of the demonstrate any significant effect of stimulators and of blockers in alpha and alpha -adrenergic receptor in the airways resistance. This tracheobronchial system, in comparison to Hexoprenaline (beta2- 1 2 adrenergic agonist) and Ipratropium bromide (anticholinergic), which suggests that the activity of alpha1 and alpha2-adrenergic receptor in are very effective in the removal of increased bronchomotor tonus, by the smooth bronchial musculature and in the epithelial part of airways causing significant decrease of the resistance (Raw), respectively of is not a primary mechanism which to cause response in patients with specific resistance (SRaw) (p < 0.01). See Figure 2, 3, 4 and 5. Changes middle and severe bronchial reactibility.

4 Flow [L/s] F/V ex 2.0 Flow [L/s] Mouth pressure [kPa] 3 2.5 1.5 2.0

2 1.0 1.5

1.0 1 0.5 0.5

0 1 0.0 0.0 0.5 1.0 1.5 2.0 2.5 -0.5 1 -0.5 -1.0

-1.0 -1.5 2 -2.0 -1.5 3 -2.5

-2.0 Volume shift[ml] 4 F/V in

a. Measurement of parameters of the gas volume in the sternum (ITGV); registration of curve flux-volume (inspiratory flux and expiratory flux - L/min); b. Resistance of airways (Raw - L/sec.) expressed in kPa. Figure 1: Measurement with Body plethysmography.

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6 6 5 5 4 4 Raw Raw 3 3 ITGV 2 ITGV 2 1 SRaw 1 SRaw SRaw (kPa x sec.) (kPa SRaw SRaw (kPa x sec.) 0 0

15’ 30’ 60’ 15’ 30’ 60’ 15’ 30’ 60’ 15’ 30’ 60’

Initial value Initial value

after Tolazoline 20 mg after Hexop. (0.2 mg) 5’after Oksedrine, 120 mg 5’after Ipratrop.(0.25 mg) 5’ 5’

TIME TIME Figure 2: Action of Oxedrine tartrate and Ipratropium in SRaw in persons with Figure 5: Action of Tolazoline and Hexoprenaline in SRaw in persons with se- middle reactibility (X ± SEM). vere reactibility (X ± SEM).

an increase of cholinergic and alpha-adrenergic response towards 6 different stimulators [18]. 5 4 Raw Despite the theory of Szentivany, which considers that the 3 adrenergic system activity is decreased, our results show that the activity 2 ITGV of the beta -adrenergic receptor is increased in order to contra pose 1 SRaw 2 SRaw (kPa x sec.) 0 cholinergic constrictor impulses in patients with increased bronchial reactibility. Meanwhile, the activity of alpha-adrenergic receptor is not 15’ 30’ 60’ 15’ 30’ 60’ important in this mechanism. Initial value Research on effect of the phentolamine in patients with bronchial asthma has not registered any changes of lung functional tests 5’after Hexop. (0.2 mg) 5’after Oxedrine, 120 mg parameters (FEV1, GAV/WL; V25 and V ERV2) by ascertaining that the increased activity of alpha-adrenergic receptor is not the central TIME mechanism in causing of the asthma disease and by emphasizing Figure 3: Action of Oxedrine tartrate and Hexoprenaline in SRaw in persons with severe reactibility (X ± SEM). the dominant role of beta2 receptor agonists [19]. Nonetheless, this author presents that asthmatic patients included in the research have manifested heterogenic response to phentolamine by categorizing 6 these patients with positive reaction, patients with negative reaction 5 and patients without reaction to phentolamine. This author assumes

4 Raw that this different reaction to phentolamine is as a result of the different 3 ITGV relation of the activity of beta adrenergic receptor, alpha adrenergic SRaw 2 and cholinergic receptor at the bronchial tree [19]. Blockage of alpha- SRaw (kPa x sec.) (kPa SRaw 1 adrenergic receptor through the application of phentolamine has no 0 significant impact to the reaction of the airways smooth musculature

15’ 30’ 60’ 15’ 30’ 60’ to histamine. Although, in some of patients with asthma are registered improvements of lung functional tests (FEV ) but without any Initial value 1 significant impact [20]. Role of the phentolamine in the airways tonus after Tolazoline 20 mg 5’ after lpratrop. (0.25 mg) 5’ should not be totally eliminated because systemic administration of TIME phentolamine causes the increase of the incidence, rate and amplitude of respiratory movements of sheep fetus in utero during hypoxia. This Figure 4: Action of Tolazoline hydrochloride and Hexoprenaline in SRaw in persons with middle reactibility (X ± SEM). proves regarding relation of phentolamine in the central mechanisms of breathing, also [21]. Phentolamine dose not cause the myorelaxant Bronchial tree of a healthy person have equilibrium of the alpha- effect following the induction of bronchoconstriction from the inhalatory therapy with metakolin and histamine in the experiment adrenergic and beta2-adrenergic system activity in the favor of with apes. Isoprenaline has manifested direct myorelaxant effect domination of beta2-receptor activity. Due to this fact, it is assumed that following the induction of bronchoconstriction with aerosol therapy in case of hypoactivity of the beta2-adrenergic system dominates alpha- adrenergic system, thus it was supposed that this mechanism plays the with metakolin and histamine. Meantime, atropine has manifested the main role in the bronchoconstriction in patients with bronchial asthma partial bronchodilator effect only after inhalation of metakolin yet not [17]. after the inhalatory therapy with histamine [22]. According to Szentivan, increased bronchial irritability of airways Results of this research, and of other authors also, indicate related in asthmatics is caused by the autonomous disbalance, which derives to the pharmacologic relevance of beta2 agonists (Hexoprenaline) and from the decreased beta-adrenergic function, and which results with anti-cholinergic substances (Ipratropium) in improvement of lung

Page 5 of 8 functional test values in patients with asthma and chronic obstructive blockade of alpha and beta-receptors in intrinsic bronchial asthma. Clin Allergy diseases [22]. 3: 439-448. 10. Mathé AA, Aström A, Persson NA (1971) Some bronchoconstricting and All of these results suggest that role of Oxedrine and Tolazoline broncho-dilating responses of the isolated human bronchi: evidence for the depends directly on the presence and structural extension of alpha existence of alpha-adrenereceptors. J Pharm Pharmacol 23: 905-910. adrenergic receptor, respectively from two sub-types of these receptors. 11. Lux R, Awa W, Walter U (2009) An interdisciplinary analysis of sex and gender Therefore, further researches of the configuration and sub-types in relation to the pathogenesis of bronchial asthma. Respir Med.103: 637-649. of these receptors would help out in a clearer defining of the role of 12. Dergacheva O, Griffioen KJ, Neff RA, Mendelowitz D (2010) Respiratory these receptors in the pathophysiologic mechanism of asthma and modulation of premotor cardiac vagal neurons in the brainstem. Respir Physiol pulmonary obstructive diseases. Neurobiol 174:102-110. 13. Leff AR, Munoz NM (1981) Evidence for two subtypes of alpha adrenergic Conclusion receptors in canine airway smooth muscle. J Pharmacol Exp Ther 217: 530- 535. Based on obtained results, it can be concluded as follows: 14. Grundström N, Andersson RG, Wikberg JE (1984) Inhibition of the excitatory • Inhalation of Oxedrine (120 mg-aerosol), stimulator of alpha1- non-adrenergic, non-colinergic neurotransmission in the guinea-pig adrenergic receptor applied to the patients with middle and tracheobronchial tree mediated by alpha2-adrenoceptors. Acta Pharmacol severe bronchial reactibility does not change the increase of the Toxicol (Copenh) 54: 8-14. specific resistance (SRaw) of airways (p > 0.1). 15. Andersson RG, Fügner A, Lindgren BR, Muacevic G (1986) Inhibitory effects of clonidine on broncospasm induces by vagal stimulation or antigen challenge in guinea-pigs. Eur J Pharmacol 123: 181-185. • Application of Tolazoline (20 mg-aerosol), as blocker of alpha2- adrenergic receptor applied to the patients with middle and 16. Lindgren BR, Ekström T, Andersson RG (1986) The effect of inhaled clonidine severe bronchial reactibility also does not change the decrease of in patients with asthma. Am Rev Respir Dis 134: 266-269. the specific resistance (SRaw) of airways (p > 0.1). 17. Hendersson WR, Shelhamer JH, Reingold DB, Smith LJ, Evans R, et al. (1979) Alpha-adrenergic hyper-responsiveness in asthma. N Engl J Med 300: 642- • Application of Hexoprenaline through inhalation to the patients 647. with middle and severe bronchial reactibility causes significant decrease of specific resistance (SRaw) of airways (p < 0.01). 18. Szentivany A (1968) The beta adenergic theory of atopic abnormality in bronchial asthma. J Allergy 42: 203.

• Ipratropium as antagonist of the cholinergic system applied as 19. Shiner RJ, Molho MI (1983) Comparison between an alpha-adrenergic aerosol in patients with middle and severe bronchial reactibility antagonist and beta2-adrenergic agonist in bronchial asthma. Chest 83: 602- also causes significant decrease of specific resistance (SRaw) of 606. airways (p < 0.01). 20. Walden SM, Bleecker ER, Chahal K, Britt EJ, Mason P, et al. (1984) Effect of alpha-adrenergic blockade on exercise-induced asthma and conditioned cold • This suggests that the application of agonists and antagonists in air. Am Rev Respir Dis 130: 357-62.

patients with middle and severe bronchial reactibility does not 21. Giussani DA, Moore PJ, Bennet L, Spencer JA, Hanson MA (1995) Alpha change the activity of alpha and alpha adrenergic receptor 1 1 2 and alpha2-adrenoreceptor actions of phentolamine and prazosin on breathing in the smooth bronchial musculature and it is not a primary movements in fetal sheep in utero. J Physiol 486: 249-255. mechanism which causes reaction in patients with middle and 22. Mue S, Ohmi T, Suzuki S, Tamura G, Hida W, et al. (1983) The Effect of severe bronchial reactibility. There is a possibility that sub- Adrenergic and Cholinergic on Methacholine- and Histamine-Induced Bronchoconstriction in Monkeys Drugs. Tohoku J Exp Med 140: 109-119. types of alpha1 and alpha2 adrenergic receptors persist, yet in insufficient size to react significantly with agonist and antagonist alpha-adrenergic substances. References 1. Barnes PJ (1989) Mechanisms of Disease: Airway receptors. Postgrad Med J 65: 532-542.

2. Krop M, Ozünal ZG, Chai W, de Vries R, Fekkes D, et al. (2010) Mast cell degranulation mediates bronchoconstriction via serotonin and not via renin release. Eur J Pharmacol.640: 185-189.

3. Gross NJ (1988) Ipratropium bromide. N Engl J Med 319: 486-494.

4. Jooste E, Zhang Y, Emala CW (2007) Neuromuscular Blocking Agents’ Differential Bronchoconstrictive Potential in Guinea Pig Airways. Anesthesiology 106: 763-772.

5. Islami H, Krasniqi S, Ahmetaj H, Haliti N, Kurtishi I, et al. (2011) Phentolamine action in permeability of airways at patients with bronchial asthma. Med Arh 65: 4-8.

6. Gross GN, Souhrada JF, Farr RS (1978) The long-term treatment of asthmatic patients using phentolamine. Chest. 66:397-401.

7. Black JL, Temple DM, Anderson SD (1978) Long-term trial of an alpha adrenoceptor blocking drug (indoramine) in asthma Scand J Respir Dis 59:307- 312.

8. Rosenthal RR, Kondarskky DW, Rosenberg GL, Norman PS (1976) The role of alpha-adrenergic receptors in allergic asthma. J. AllergClin. Immunol 57: 223.

9. Patel KR, Kerr JW (1973) The airways response to phenylephrine after

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